Functional beta cell mass is regulated by processes that either increase the size and number of insulin- secreting pancreatic beta cells or destroy beta cells as well as the secretory capacity of individual beta cells. A loss of functional beta cel mass is required for the development of both type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively). The current application addresses the critical need to establish methods to protect and/or restore functional beta cell mass to combat T2DM. The goals of the proposed work are to identify pathways that can be exploited to stimulate beta cell growth, promote beta cell survival, maintain beta cell function, and ultimately restore functional beta cell mass. We have become interested in molecular brakes for beta cell proliferation and are keen to demonstrate that these brakes also play an important role in beta cell survival and function. Through our work we discovered that Mig6 is induced during beta cell stress where it not only impairs beta cell proliferation but also induces apoptosis. Mig6 is an anti-proliferative endogenous its established roles as a molecular brake for proliferation and emerging role as a brake for pro- survival signaling pathways, we hypothesize that ablation of Mig6 will increase or at least protect functional beta cell mass in vivo. To this end, the following specific aims are proposed: 1) to define how Mig6 abrogates pro-survival signaling in the beta cell, 2) to demonstrate how Mig6 regulates functional beta cell mass during the development of T2DM, and 3) to establish how Mig6 impairs beta cell function. Experiments will be conducted in beta cell lines (when necessary), isolated rodent (rat and mouse) and human islets, and a mouse model of beta cell-specific deletion of Mig6. The proposed work will identify new pathways than can be therapeutically targeted to prevent or treat T2DM.